Safety, pharmacokinetics and efficacy of selumetinib in Chinese adult and paediatric patients with neurofibromatosis type 1 and inoperable plexiform neurofibromas: The primary analysis of a phase 1 open‐label study

We present data from a phase 1 study (

and paediatric; Figure 1).We present data from the primary analysis, which was required for selumetinib registration in China, and was performed after the last dosed patient had completed their cycle 10 visit (data cut-off [DCO] 16 August 2022).At primary DCO, patients were expected to have completed two post-baseline response assessments (at cycles 4 and 8).
Overall, 16 adult and 16 paediatric patients received selumetinib (Table 1).One adult discontinued treatment due to the patient's decision but remained on the study; all paediatric patients continued to receive treatment at primary DCO.The reported safety profile was consistent with the known safety profile of selumetinib. 5,6All patients in the study experienced adverse events (AEs); most experienced treatment-related AEs (Table 2).The most common AEs in the adult and paediatric cohorts were dermatitis acneiform (n = 13; 81%) and pyrexia (n = 6; 38%), respectively; all were grade 1/2 events and were reported in SPRINT. 4,5The most common treatment-related AEs were dermatitis acneiform (n = 13; 81%) in adult patients, and decreased blood albumin and paronychia in paediatric patients (both, n = 4; 25%).One (6%) adult patient reported a serious adverse event (SAE; grade 3 pulmonary tuberculosis, not treatment related) leading to dose interruption.One (6%) adult patient experienced an AE leading to dose reduction and two (13%) experienced AEs leading to dose interruption (Table 2).One (6%) paediatric patient reported SAEs (two grade 3 sepsis and one grade 3 urinary tract infection, neither were treatment related).Three (19%) paediatric patients experienced AEs leading to dose interruption; none experienced AEs leading to dose reduction (Table 2).Two (13%) adult patients and one (6%) paediatric patient reported grade ≥3 AEs; similar to SPRINT phase F I G U R E 1 Study design.† Inoperable PN were defined as PN that cannot be completely removed by surgery without risk of substantial morbidity due to encasement of, or close proximity to, vital structures, invasiveness, or high vascularity of the PN.‡ Patients must have had ≥1 measurable PN (≥3 cm).The target PN (refer to Supporting Information for further information) was defined as the most clinically relevant PN; only one non-target PN could be selected, if any.Intensive PK samples were collected after single and multiple dosing.The SRC evaluated preliminary tolerability and safety data, and PK data (if available) after the first six patients in both cohorts had approximately three cycles of treatment.Additional enrollment was initiated per SRC recommendation.Long-term post-treatment safety follow-up assessments will be conducted for 1 year (at 6-and 12-month post-treatment) for paediatric patients only.Abbreviations: AE, adverse event; AUC, area under the concentration-time curve; BSA, body surface area; C max , maximum plasma concentration; DCO, data cut-off; ECG, electrocardiogram; ECHO, echocardiogram; HRQoL, health-related quality of life; ICR, independent central review; MEK, mitogen-activated protein kinase kinase; MPNST, malignant peripheral nerve sheath tumour; NF1, neurofibromatosis type 1; ORR, objective response rate; PGIC, patient's global impression of change; PGIS, patient's global impression of severity; PK, pharmacokinetics; PN, plexiform neurofibroma; PS, performance status; RAF, rapidly accelerated fibrosarcoma; RAS, rat sarcoma; REiNS, response evaluation in neurofibromatosis and schwannomatosis; SRC, Safety Review Committee; T max , time to reach maximum plasma concentration.increased blood creatine phosphokinase and paronychia, were grade 1/2. 4 No grade 4 AEs were reported at primary DCO; no AEs led to death or selumetinib discontinuation.No unexpected clinically significant trends of change were observed for laboratory assessments, vital signs or electrocardiogram/echocardiogram in either cohort.No abnormal reports of bone growth or Tanner stages were reported in the paediatric cohort.
Selumetinib was rapidly absorbed in both cohorts; median (range) time to reach maximum plasma concentration (T max ) at steady state was 1.5 h (.5-1.6 h) and 1.5 h (.5-3.0 h) in the adult and paediatric cohorts, respectively (Table 3).In adults, the median (range) T max for a single dose (1.0 h [.5-1.5 h]) and at steady state (1.5 h [.5−1.6 h]; Table 3) observed in this study showed similarity with those published for White (1.0 h [1.0−4.0 h]) and Asian (1.0 h [1.0−4.0 h]) patients in a pooled analysis of healthy subjects. 8In adult and paediatric cohorts, the metabolite-to-parent ratios of area under the concentration-time curve (AUC) from time 0−12 h at steady state (AUC 0−12 h,ss ) and maximum plasma concen-tration (C max ) at steady state (C max,ss ) were ≤.074 and ≤.085, respectively, indicating a higher exposure to selumetinib than its active metabolite, N-desmethyl selumetinib.The single-dose C max reported in the paediatric and adult cohorts were 871 and 1285 ng/mL, respectively (Table 3).A rapid elimination profile was observed in both cohorts; selumetinib had a mean half-life of 7.49 and 7.20 h in adult and paediatric patients, respectively.There was no obvious accumulation after multiple dosing.In the adult cohort, AUC 0−12 h,ss and C max,ss accumulation ratios were 1.34 and .96,respectively.In the paediatric cohort, AUC 0−12 h,ss and C max,ss accumulation ratios were 1.51 and 1.29, respectively.Selumetinib had a systemic exposure temporal change parameter of AUC ≤1.13 and ≤1.26 in the adult and paediatric cohorts, respectively (Table 3).Low-to-moderate variability of PK exposure was observed in adult patients at steady state with a geometric coefficient of variation (gCV) of 20%−32% for AUC 0−12,ss and C max,ss for selumetinib and its metabolite.In paediatric patients, moderate variability of PK exposure was observed at steady state with a gCV ranging from 32% to 44% for AUC 0−12 h,ss and C max,ss  for selumetinib and its metabolite (Tables 3 and S1).The observed selumetinib PK profile was similar to that seen in SPRINT 9 and in a phase 1 Japanese trial. 10PK parameters of N-desmethyl selumetinib are in Table S1.The geometric mean plasma concentration-time profiles are shown in Figure S1.Selumetinib showed promising efficacy and improvements from baseline in health-related quality of life in both cohorts (Supporting Information).Efficacy was a secondary endpoint.Therefore, these first published adult efficacy data should be interpreted with caution and considered preliminary.Efficacy and safety of selumetinib in adults with NF1-PN are being assessed in an ongoing randomised, double-blind, placebo-controlled, two-arm, global phase III study (KOMET; NCT04924608; 146 participants).
TA B L E 2 Adverse event (AE) profile in adult and paediatric patients at primary data cut-off (16 August 2022; after the last dosed patient completed cycle 10, day 28).Abbreviations: D-j, double j; SAE, serious adverse event.

Patients experiencing AEs
a Grade 3 paronychia considered to be treatment related and grade 3 pulmonary tuberculosis not considered to be treatment related.
b Interruption or reduction.c Grade 3 paronychia (treatment related; dose interruption and subsequent dose reduction), grade 2 haematoma (treatment related; dose interruption) and grade 3 pulmonary tuberculosis (not treatment related; dose interruption).d Grade 3 paronychia (treatment related; dose interruption and subsequent dose reduction) and grade 2 haematoma (treatment related; dose interruption).
e Two instances of grade 3 sepsis and one instance of grade 3 urinary tract infection (possibly due to D-j urethral catheterisation) that led to dose interruption; these were not considered to be treatment related.

TA B L E 3
Selumetinib pharmacokinetics (PK) parameters following single and multiple doses.Abbreviations: AriMean, arithmetic mean; AUC 0−12 h , area under the concentration-time curve from time 0−12 h; AUC inf , area under the concentration-time curve from zero to infinity; AUC last , area under the concentration-time curve from zero to the last measurable concentration; C max , maximum plasma concentration; gCV, geometric coefficient of variation; GeoMean, geometric mean; R ac AUC 0−12 h , accumulation ratio based on AUC 0−12 h ; R ac C max , accumulation ratio based on C max ; SD, standard deviation; t 1/2 λ z , terminal elimination of half-life; TCP, temporal change parameter in systemic exposure; T max , time to reach maximum plasma concentration.

Single dose
Overall, within context of limitations (single-arm trial, small sample size), this study demonstrated that selumetinib has an acceptable benefit-risk profile.Therefore, selumetinib may address the unmet medical need for patients with NF1-PN in China.

D ATA AVA I L A B I L I T Y S TAT E M E N T
Alexion will consider requests for disclosure of clinical study participant-level data, provided that participant privacy is assured through methods such as data deidentification, pseudonymisation or anonymisation (as required by applicable law), and if such disclosure was included in the relevant study informed consent form or similar documentation.Qualified academic investigators may request participant-level clinical data and supporting documents (statistical analysis plan and protocol) pertaining to Alexion-sponsored studies.Fur-ther details regarding data availability and instructions for requesting information are available in the Alexion Clinical Trials Disclosure and Transparency Policy, available at https://alexion.com/our-research/research-anddevelopment.Link to data request form: https://alexion.com/contact-alexion/medical-information.

E T H I C S S TAT E M E N T
The clinical study protocol and participant informed consent documents were submitted to the Ethics Committee for review and were approved before the initiation of the study (paediatric, XHEC-A-2020-019-1; adult, SH9H-2020-C9-3).All the participants provided written informed consent.

C O N S E N T F O R P U B L I C AT I O N
All authors declare that they agree to publish this present manuscript with no conflicts of interest.

TA B L E 1
Baseline demographics and clinical characteristics.

A
C K N O W L E D G E M E N T S Medical writing support for the development of this manuscript, under the direction of the authors, was provided by Connie Feyerherm, MSci, and Emily Clark, PhD, of OPEN Health Communications (London, UK) and funded by Alexion, AstraZeneca Rare Disease and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, in accordance with Good Publications Practice 2022 guidelines.We would like to acknowledge the SPRINT study team for providing data from their clinical trial used in this manuscript.The SPRINT study (NCT01362803) led by Drs.Brigitte Widemann and Andrea Gross was sponsored by the NCI Cancer Therapy Evaluation Program, and conducted under a Cooperative Research Development Agreement between NCI and AstraZeneca with additional support from the Neurofibromatosis Therapeutic Acceleration Program and the Children's Tumor Foundation.This study was funded by AstraZeneca as part of an alliance between AstraZeneca and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.C O N F L I C T O F I N T E R E S T S TAT E M EN T Z.W. and Q.L. received research grants from the National Natural Science Foundation of China and the Science and Technology Commission of Shanghai Municipality.Z.W., X.Z., C.L., X.G., Y.L., J.Z., X.Y. and Q.L. received support for the clinical study from AstraZeneca as part of an alliance between AstraZeneca and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, editorial/medical writing assistance from Connie Feyerherm and Emily Clark of OPEN Health Communications (London, UK), and financial support from Alexion, AstraZeneca Rare Disease.J.Z., Y.L., X.G. and C.L. report employment at AstraZeneca.